New Approaches to Catalyst Screening and Development

催化剂筛选和开发的新方法

基本信息

批准号：
2102705
负责人：
David Hage
金额：
$ 57.5万
依托单位：
University of Nebraska-Lincoln
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2102705&HistoricalAwards=false
关键词：
New Approaches Catalyst Screening Development

项目摘要

This research project builds on a platform being developed by the University of Nebraska research team to exploit enzymes as catalytic reporters to facilitate reaction discovery and catalyst optimization. This approach is termed In Situ Enzymatic Screening. The method utilizes ‘reporting enzymes’ to provide real-time information on the relative rates for a set of parallel organic/organometallic reactions of interest. Parallel screening methods are of interest to chemists in academia and industry as they enable the identification of fundamentally new transformations of novel catalysts for targeted reactions. There is a particular need for focused screening in process chemistry groups in the pharmaceutical industry, where reaction optimization is critical. This project seeks to develop new enzymatic screening tools that are applicable across a range of temperatures and that take advantage of phosphate ester functionality for which enzymatic screens are not yet available. The project will also help build the future STEM (science, technology, engineering, and mathematics) workforce by training a diverse group of undergraduate and graduate students in an interdisciplinary research environment at the chemistry/biology interface, including elements of organic, organometallic, analytical, and enzymatic chemistry. This project will further explore and develop an information-rich parallel screening method, termed In Situ Enzymatic Screening (ISES), that uses enzymes as biomacromolecular sensors to provide read-out directly to the experimentalist. This research builds upon the team's earlier proof-of-concept studies that led to the first examples of catalytic asymmetric allylic amination chemistry with nickel, an earth-abundant metal, and that uncovered a useful new transformation for diversity-oriented synthesis known as thiocyanopalladation/carbocyclization. This proposal seeks to fully launch the ‘phosphate-ISES’ and ‘thermal-ISES’ screening platforms. The former goal is motivated by the emergence and importance of substrates bearing dialkyl phosphate functionalities, an important functional group both for transition metal coordination and for specific chemistry. These new enzymatic screening platforms have been built by expressing and testing candidates for screening enzymes that recognize dialkyl phosphates and/or that operate at elevated temperatures. Preliminary results point to enzymes that produce a UV/vis signal under such conditions, enabling the screening of candidate metal-ligand combinations at elevated temperatures or in reactions where dialkyl phosphate functionalities are critical. These methods are being developed with specific targeted chemistry in mind, particularly the catalytic asymmetric synthesis of alpha-halovinyl amino acids as potential mechanism-based inhibitors for PLP (pyridoxal phosphate) enzymes. This synthetic goal builds on recent developments in this laboratory in which quaternary, alpha-(1’-fluoro) vinyl amino acids were synthesized for the first time. The scientific broader impacts of this work include opening new avenues for the catalyst discovery process and for green and sustainable chemistry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该研究项目建立在由内布拉斯加州大学研究团队开发的平台上，以利用酶为催化记者，以促进反应发现和催化剂优化。这种方法称为原位酶筛选。该方法利用“报告酶”提供有关一组并行有机/有机金属反应的相对速率的实时信息。平行筛选方法是学术界和工业中的化学家感兴趣的，因为它们能够鉴定出针对目标反应的新型催化剂的根本新转变。在制药行业的过程化学组中，特别需要重点筛查反应优化至关重要的过程。该项目旨在开发新的酶筛选工具，这些工具适用于一系列温度，并利用磷酸酯功能尚不可用的磷酸酯功能。该项目还将帮助建立未来的STEM（科学，技术，工程和数学）劳动力，通过在化学/生物学界面的跨学科研究环境中培训一个潜水的本科生和研究生组，包括有机，器官，分析，分析和酶促化学的元素。该项目将进一步探索和开发一种以原位酶筛选（ISE）为单位的富含信息的并行筛选方法，该方法将酶用作生物乳粒分子传感器，以直接向实验者提供读出。这项研究基于该团队的较早概念验证研究，该研究导致了用镍（镍（一种土壤丰富的金属））进行催化不对称的非对称倾向胺化学的例子，并发现了一种有用的新的转化，用于多样性的合成，称为硫代苯基抗体抗逆化/碳细胞化。该提案旨在完全启动“磷酸盐”和“热效”筛选平台。前者的目标是由载有磷酸二甲基功能的底物的出现和重要性激励，这是过渡金属协调和特定化学反应的重要功能组。这些新的酶筛选平台是通过表达和测试筛查酶来识别二甲基磷酸盐和/或在升高温度下运行的酶的候选构建的。初步结果表明，在这种条件下产生紫外线/VIS信号的酶，可以在升高温度或二甲基磷酸盐功能至关重要的反应中筛选候选金属配体组合。考虑到特定的靶向化学，尤其是将α-甲维涅氨基酸作为基于PLP的潜在机制抑制剂（吡啶还源磷酸）酶催化不对称合成的催化不对称合成。这个合成目标建立在该实验室的最新发展上，该实验室首次合成了第四纪α-（1'-氟）乙烯基氨基酸。这项工作的科学广泛影响包括为催化剂发现过程和绿色和可持续化学的新途径开放新途径。该奖项反映了NSF的法定任务，并通过使用基金会的知识分子和更广泛的影响评估标准来评估，被认为是珍贵的支持。